The cat RDS transcript: candidate gene analysis and phylogenetic sequence analysis.

Abstract

Mammalian Genome 4, 544-548 (1993). e//o///e 9 Springer-Verlag New York Inc. 1993 The cat RDS transcript: candidate gene analysis and phylogenetic sequence analysis Michael B. Gorin, I Steven Snyder, 2 Agnes To, 1 Kristina Narfstrom, 3 Roger Curtis 4 1The Eye & Ear Institute of Pittsburgh, Departments of Ophthalmology and Human Genetics, 203 Lothrop Street, University of Pittsburgh School of Medicine and Graduate School of Public Health, Pittsburgh, Pennsylvania 15213, USA 2Department of Ophthalmology, University of Indiana, Indianapolis, Indiana, USA 3Department of Medicine and Surgery, Swedish University of Agricultural Sciences, Uppsala, Sweden 4Comparative Ophthalmology Unit, Animal Health Trust, Suffolk CB8 7PN, UK Received: 10 May 1993 / Accepted: 2 July 1993 The RDS gene (human and cat designation, rds gene in the mouse) was the first gene to be specifically iden- tiffed with a mammalian hereditary retinal degenera- tion (Travis et al. 1989). Also known as peripherin (Connell and Molday 1990), the RDS gene has been investigated for other retinal degenerations, including the progressive rod-cone dysplasia of miniature poo- dles, and human autosomal dominant retinitis pigmen- tosa (RP). Recent reports have confirmed linkage to the orthologous RDS locus in several autosomal dom- inant RP families, and mutations in the gene have been identified (Farrar et al. 1991; Kajiwara et al. 1991). Because of the phenotypic diversity that can occur with mutations of the same gene in different species, we evaluated the RDS transcript for two retinal degen- erations that have been identified in cats--the reces- sive retinal degeneration in Abyssinian cats, rdAC, de- scribed by Narfstrom (Narfstrom 1985; Narfstrom and Nilsson 1987) and the dominantly inherited rod-cone dystrophy, Rdy, identified by Curtis (Holmes and Cur- tis 1990; Leon and Curtis 1990; Leon et al. 1991), that is also present in the Abyssinian breed. In cats homozygous for the rdAC, ultrastructural alterations can be seen in photoreceptors even prior to retinal maturation (Narfstrom and Nilsson 1987). Vi- sual function and electrophysiology initially appear relatively intact. Ophthalmoscopic abnormalities are not evident until 1.5 years of age, and visual loss pro- gresses to complete blindness in approximately 3 years. ERG changes correlate with the loss of rhodop- sin, with no evidence that overall retinal sensitivity is The nucleotide sequence data reported in this paper have been as- signed GenBank accession number M94047. Correspondence to: M.B. Gorin reduced by other mechanisms. In this respect, the ERG changes in rdAC are comparable to those in the diffuse form of human dominantly inherited RP (Narf- strom et al. 1989). The onset and progression of retinal disease are considerably slower than that associated with the murine rd and rds mutations or the rod-cone dysplasias of the Irish setter or collies and comparable to the progressive rod-cone degeneration in miniature poodles (O'Brien and Aguirre 1987). The combination of electrophysiology, visual pigment reflectometry, light and ultrastructural histology all indicate that this recessive retinal disorder is primarily localized to a defect in the photoreceptors, with the initial distur- bances being localized to the rods with later degener- ation of the cones. The dominant rod-cone dysplasia, Rdy, exhibits rod and cone abnormalities from the earliest age ex- amined (2 weeks). Degenerative changes become evi- dent at 4.5 weeks as the photoreceptors, which have only rudimentary outer segments, develop pyknotic nuclei and cellular displacement into the subretinal space. The degeneration begins centrally and spreads peripherally with progressive photoreceptor cell loss. Vision is profoundly affected in the early stages of the disease, and blindness becomes total within a few months. Like the rdAC model, both histological and biochemical evidence suggest that the primary defect resides in the photoreceptors. Candidate gene analysis of the RDS transcript in these two animal models of retinal disease with cross- species RT/PCR can determine whether point muta- tions in this gene could play a causative role for either of these conditions. The R D S is an excellent candidate gene for these feline retinal degenerations because, as discussed above, the rdAC and Rdy degenerations ap- pear to be photoreceptor-specific and the R D S gene